2-fluoro-2-phenylmalonamide



United States Patent Ce 3,141,040 Z-FLUORQ-Z-PHENYLMALONAMIDE Charles E.Inman, Glenside, Robert E. Oesterling, Flourtown, and Edward A.Tyczkowski, Abington, Pa., assignors to Pennsalt Chemicals Corporation,Philadelphia, Pa., a corporation of Pennsylvania No Drawing. Originalapplication Sept. 22, 1958, Ser. No. 762,248, now Patent No. 3,030,408,dated Apr. 17, 1962. Divided and this application Feb. 19, 1962, Ser.

1 Claim. (Cl. 260558) is a stable fluorine derivative of perchloricacid. (H. Bode and E. Klesper, Z. Anorg. u. Allgem. Chem, 225, 275(1951), and A. Engelbrecht and H. Atzwanger, Monatsh. 83, 1087 (1952).Its chemical reactivity with organic compounds has heretofore beenunknown.

We have now found that the alpha hydrogen atoms of an active hydrogencompound (an organic compound containing active hydrogen) can bereplaced readily by fluorine atoms by contacting said active hydrogencompound With an alkali metal base and with perchloryl fluoride in aninert diluent which is substantially non-reactive under the conditionsexisting in the reaction zone at a temperature below 250 C. untilreaction therebetween substantially occurs to form the fluorinatedderivative of the active hydrogen compound, which is then recovered fromthe reaction mass.

An active hydrogen compound is defined in the art as an organic compoundwhose essential structural feature comprises a carbon atom to which isattached by covalent attachment at least one hydrogen atom and at leastone functional group, or common electron-accept ing group, such ascarbonyl, nitrile, nitro, etc. (Reynold C. Fuson, Advanced OrganicChemistry, John Wiley & Sons, Inc., NY. (1950), Chap. XVIII). The saidcarbon atom in said compound is defined as being in alpha position withrespect to said functional group, and the hydrogen attached to thecarbon is referred to as alpha, or active, hydrogen. The concept ofactive hydrogen is old in organic chemistry theory and has been definedin the art in terms of a form of chemical behavior characteristic ofactive hydrogen compounds. According to theory dealing with thestructure and reactivity of organic compounds, the polarity of theelectron-accepting group furnishes the driving force for the increasedactivity of the hydrogen.

Halogenation of an active hydrogen compound to replace the alphahydrogen with iodine, chlorine and bromine is old in the art. Twomethods are known in the art for the substitution of iodine, chlorineand bromine for the alpha hydrogen of an active hydrogen compound. Inthe first of these methods, the organic compound is treated withmolecular halogen, e.g., I C1 or Br in the presence of a catalyst, suchas the halides of sulfur and phosphorus, or sunlight. In the secondmethod, the said organic compound is treated with the said molecularhalogen in the presence of an alkali, e.g., alcoholic KOH, to form thehalogenated compound.

Unlike halogenation with the other halogens, direct halogenation of anactive hydrogen compound with fluo- 3,141,040 Patented July 14, 1964rine is not practical because of the high reactivity of fluorine.Fluon'nation, as for example with elemental F results in the replacementnot only of the alpha hydrogen atoms of an alpha carbon of the compoundbut also in the introduction of fluorine into the functional group orgroups present. Cleavage of the C to C bonds may also result. It isknown in the art that a fluorinated active hydrogen compound can be madeby an indirect method involving a number of steps. For example, Henneand DeWitt, J. Am. Chem. Soc. 70, 1548 (1948), describe a procedurewhereby they prepare difluoromalonic acid and some of its derivativesfrom malonie acid, a typical active hydrogen compound, by a multiplestep process including chlorination, fluorination, dehydrochlorinationand oxidation.

In contrast the reaction involved in our invention is quite simple, asshown below in a typical reaction using diethyl malonate as the activehydrogen compound, sodium ethylate as the alkali metal base, perchlorylfluoride as the fiuorinating agent, and ethanol as the inert diluent:

Although not a strictly accurate statement of the mechanism, thereaction may be visualized as taking place in two steps, sodium from thebase first replacing active hydrogen, and fluorine then replacing thesodium.

The fluorination method of our invention is broadly applicable toreplacing with fluorine the alpha hydrogen atoms of an active hydrogencompound having the forrnula wherein R, Q, and T represent hydrogen; oran aliphatic radical of not more than 12 carbon atoms, the carbonskeleton of which has attached to it radicals selected from the groupconsisting of hydrogen and halogen; or a functional group sufficientlyelectronegative to render said active hydrogen compound capable offorming an alkali metal substituent of said compound by replacement ofsaid alpha hydrogen atoms with alkali metal atoms; and at least two ofR, Q, and T are said functional group.

Examples of the said functional groups R, Q, and T which may be presentin the active hydrogen compound reactant t R(|3T N and in the finalfluoro-organic product include X X /X CN; -=0; o=c

OX 0X X =0; ES; C=S; and NO2 wherein X, Y, and Z represent hydrogen,halogen, phenyl,

or an aliphatic radical of not more than 3 carbon atoms,

such as by reacting potassium chlorate with elemental fluorine or byelectrolysis of sodium perchlorate in anhydrous hydrofluoric acid, asdescribed in the references cited above.

The alkali metal base used in practicing our invention may be an alkalimetal, or the alkoxide, hydroxide, hydride or amide of an alkali metal.Examples of alkali metals are sodium, potassium and lithium. Examples ofalkali metal alkoxides are sodium methoxide; sodium ethoxide; which arepreferred; sodium propoxide; sodium butoxide; potassium methoxide;potassium ethoxide; potassium propoxide; lithium methoxide; lithiumethoxide; lithium propoxide; and lithium butoxide. Examples of alkalimetal hydrides are sodium hydride, potassium hydride, and lithiumhydride. Examples of alkali metal hydroxides are sodium hydroxide, whichis preferred; potassium hydroxide; and lithium hydroxide. Examples ofalkali metal amides are sodium amide, which is preferred; potassiumamide; and lithium amide.

It is necessary that the base used in carrying out our invention havesuflicient basicity to remove the alpha hydrogen, which is acidic incharacter, from a particular active hydrogen compound. The degree ofbasicity required by the alkali metal base is predictable from theacidity of the alpha hydrogen of the active hydrogen compound. As isWell known in the field of organic chemistry, the acidic character of analpha hydrogen is dependent on the number of functional groups attachedto the alpha carbon. The relative basicity of the alkali metal bases isalso well-known. Thus, the amides are more basic than the alkoxides,which in turn are more basic than the hydroxides. In selecting the baseto use with a particular active hydrogen compound for practicing ourinvention, a strong base is selected for use with a weakly acidic activehydrogen compound and a weak base is selected for use with a stronglyacidic active hydrogen compound.

The reactions of this invention are carried out in a nonaqueous solventor diluent which preferably is inert to the reactants and to theproducts formed. Examples of such solvents and diluents are methanol,ethanol, isopropanol, petroleum ether, and liquid aliphatichydrocarbons, e.g., hexane, ligroin, etc. However, the active hydrogencompound, when it is a liquid, can act as its own solvent.

In the practice of our invention it has been found that where a compoundpossesses more than one alpha hydrogen atom substantially all the alphahydrogen atoms of a particular active hydrogen compound will be replacedby fluorine atoms in a particular molecule, to the extent that anadequate amount of alkali metal base and an equivalent amount ofperchloryl fluoride are present, before replacement of the alphahydrogen atoms on the next molecule begins. For example, if one mole ofdi ethyl malonate, CH (COOC H is contacted with two moles of sodiumethylate and one mole of perchloryl fluoride in accordance with ourmethod, one-half mole of diethyldifluoro malonate, CF (COOC H is formedrather than one mole of diethylfluoro malonate CHF (COOC H Z This resultis inherent in the chemistry of active hydrogen compounds. Therefore, inpracticing our invention it is advantageous to use at least one mole ofperchloryl fluoride and one mole of alkali metal base for each activehydrogenation present per mole of the active hydrogen compound. Whenonly one active hydrogen atom is present, the ratio of moles ofperchloryl fluoride and of alkali metal base to moles of the activehydrogen compound required will be 1:121; for two active hydrogens, theratio required will be 2:221; and for three active hydrogens, the ratiorequired will be 3:3: 1.

The amount of solvent or diluent, when one is used, must be sufficientlyadequate, at the beginning of the reaction, to permit substantialsolution or suspension of the active hydrogen compound in the diluent.Under the conditions existing at the end of the reaction the amount ofsolvent used should be sufliciently adequate to permit easy agitationand transfer of the mixture of liquid and solid products present. Theamount of solvent which may be used is not otherwise restricted and maybe from about 3 parts by Weight to about 15 parts by weight of solventto 1 part of active hydrogen compound. This means that when the activehydrogen compound itself acts as solvent, it is used in 3-fold or moreexcess over the other reactants. Preferably about 4 to 10 parts byweight of solvent are used per part of active hydrogen compound.

The alkali metal salt of the active hydrogen compound may advantageouslyin some cases, where it is substantially stable enough to permit doingso, be prepared well in advance of the fluorination reaction by reactingthe active hydrogen compound With an alkali metal base in the same typeof solvent or diluent that is used for the fluorination step bydissolving or suspending the active hydrogen compound in the liquidmedium and then adding said base. The alkali metal salt may then beseparated for later use in the fluorination step, or it may be left inthe liquid medium and perchloryl fluoride may be added directly to it.In an embodiment of our invention an alkali metal alcoholate is preparedin an alcohol solvent by addition of an alkali metal base to saidalcohol. A stoichiometric amount of the active hydrogen compound is thengradually added to the solution of alkali metal alcoholate withagitation, followed by addition of at least a stoichiometric amount ofperchloryl fluoride. Preferably the entire amount of the salt of theactive hydrogen compound is prepared in the diluent in the reactionvessel before beginning the addition of perchloryl fluoride; however, asolution of the salt and a stream of perchloryl fluoride may beintroduced into the diluent in the reactor vessel simultaneously insubstantially stoichiometric amounts in order to maintain a readilycontrollable reaction rate and to promote efficient removal of the heatof reaction.

In practicing our invention, the perchloryl fluoride (B.P. 47.5 C.) maybe added to the reaction mass in gaseous or liquified form, preferablythe former. The rate of addition of the perchloryl fluoride should besufliciently rapid to permit the reaction to proceed, but not so rapidas to permit appreciable amounts of the gas to pass unreacted out of thereaction vessel. In approaching the end of the reaction, the perchlorylfluoride is preferably passed into the reaction mass until the mass isrendered substantially neutral, as may be determined by test with anacid-base indicator.

The reactions involved in carrying out our invention are exothermic andit is necessary that the evolved heat of reaction be removed from thereactor system. It is desirable to keep the reaction mass attemperatures sulficiently high to cause reaction to proceed at areasonable rate, but not so high as to cause undesired side reactionsand/ or decomposition of the reactants and product. Temperatures duringreaction ranging from about 15 C. to about 250 C. are satisfactory, apreferred range being between 0 C. to C. In many cases the reactionproceeds quite smoothly at ordinary temperatures, such as between 20 C.and 30 C. At ordinary temperatures water may be used as a heat transfermedium to cool the reaction vessel. At sub-zero temperatures anappropriate medium such as diethylene glycol may be used, and atelevated temperatures oil or a chemical heat transfer medium withsuitable characteristics may be used.

Pressure is not critical and the reaction may be conducted atatmospheric pressure, sub-atmospheric pressure, or super-atmosphericpressure. Atmospheric pressure is more convenient and is frequentlypreferred.

The reaction may be conducted in a vessel in batchwise fashion. In sucha case agitation of the reaction mixture is beneficial in increasing therate of reaction and angers facilitating heat transfer. The reaction maybe carried out in a semi-continuous manner in a series of connectedvessels wherein the active hydrogen compound is contacted with thealkali metal base in the first vessel and the resulting intermediatecompound is passed to one or more vessels for treatment with perchlorylfluoride. The process may also be conducted in a continuous manner byintroducing the reactants continuously into a tower or pipe systemwherein they are circulated and from which product is continuouslywithdrawn.

By-product alkali metal chlorate is formed in the reactor vessel bycombination of the alkali metal atoms released from the alkali metalbase with the ClO portion of the perchloryl fluoride molecule. Thisbyproduct chlorate crystallizes and is recovered from the reactionliquid by suitable means of separation, such as filtration.

The following examples are presented for the purpose of illustrating theinvention, it being understood that the invention is not intended to berestricted to the specific illustrative examples and that other specificmodifications are included by the invention. The parts are by weightunless otherwise stated.

Example 1 100 parts of diethyl malonate were added to 200 parts ofsodium ethylate in about 375 parts of absolute ethanol. The resultingsolution was stirred and cooled in the range of 0-10 C. Perchlorylfluoride gas was then passed into it at about room temperature until thesolution was substantially neutral to acid-base indicator. Sodiumchlorate precipitated from the solution as the reaction proceeded. Thereaction mass was filtered and the filtrate distilled at atmosphericpressure. 103 parts of crude liquid diethyl 2,2-difiuoro malonateproduct were recovered. The product was purified by distillation underreduced pressure.

The following physical constants were determined: B.P., 53 C./1 mm; B.P.184 C./atm.; N 1.3800; d. 25 C., 1.162.

Chemical analysis gave the following results for the formula C H F OCalcu1ated -C, 42.86; H, 5.14; F, 19.37. FoundC, 43.13; H, 5.27; F,17.20.

A comparison of the infrared spectra of the diethyl malonate startingmaterial and of the product produced by the action of Cl0 F on thediethyl malonate indicated the following:

The C=O ester band present in diethyl malonate at 5.71 and 5.76 1(doublet) was found to be displaced to 5.62;]. (with a shoulder at 5.67in the reaction product, a shift consistent with that expected onsubstitution of F into an ester.

The reaction product spectrum showed strong absorption in the 89.5region (at 8.7 1. and 9.37 a region in which C-F containing compoundsshow strong absorption. Diethyl malonate does not show comparable strongabsorption in this region. Thus, the C=O displacement and the strongbands in the C-F region indicate that F was now attached to the alphacarbon atom of the starting material, diethyl malonate.

Example 2 The identity of the component of Example 1 was furtherconfirmed by converting it into a known derivative, difiuoro malonamide,as follows:

The diethyl 2,2-difluoro malonate made by the method of Example 1 wasdissolved in anhydrous ethyl ether and treated with an excess ofanhydrous ammonia. A white solid was recovered which uponrecrystallization from ethanol gave white needles. On the basis ofmelting point and analysis the product was identified as difiuoromalonamide; M.P. 200-201 C. (uncorrected). Henne and De Witt, J. Am.Chem'. Soc., 70, 1548 (1948), report M.P. 205 C., corrected, for thiscompound.

6 Example 3 Following the method of Example 1, parts ofethylacetoacetate were added to about 250 parts of sodium ethylate inabout 375 parts of absolute ethanol. Upon completion of the sodiumethylacetoacetate formation, perchloryl fluoride was passed into themixture until the solution was substantially neutral.Ethyl-2,2-difiuoroacetoacetate, a novel compound, was recovered as acolorless liquid, B.P. 168 C., N 1.3975. Ethyl-2,2-difiuoroacetoaoetateis useful as an intermediate reactant in the preparation of fluorinatedderivatives of pharmaceutical compounds normally prepared fromacetoacetic acid.

Example 4 Example 5 Sixty parts of diethyl-Z-ethylmalonate were added to23 parts of sodium ethylate in about 200 parts of ethanol. Perchlorylfluoride gas was passed into the mixture at about room temperature untilthe solution was substantially neutral. Diethyl-2-ethyl-2-fluoromalonate was recovered as a colorless liquid. B.P. 48 C./0.2 mm, N=1.4121. Analysis-Calculated for M.W., 206; C, 52.42; H, 7.33. 7.31,M.W. 213.

Found: C, 54.69; H,

Example 6 The identity of the diethyl-2-ethy1-2-fluoro malonate made inExample 5 was confirmed by converting it to a fluorinated derivative ofbarbituric acid.

S-ethyl-S-fiuorobarbituric acid was formed from diethyl-2-ethyl-2-fluoromalonate according to the following reaction:

A 300 ml. stainless steel autoclave was charged with 2.62 g. of sodiumin 70 ml. of absolute ethanol, 5.1 g. of anhydrous urea, 11.7 g. ofdiethyl-2-ethyl-2-fluoro malonate, and 30 ml. of absolute ethanol. Theautoclave was heated at 122l28 C. for about 7 hours. It was then cooled.The reaction mixture was removed from the autoclave and was evaporatedunder vacuum to near dryness. The residual solid so obtained was treatedwith 20 ml. of 6 N HCl and about 20 ml. of water. The solid dissolved,but reformed after several days. 1.1 g. of solid5-ethyl-5-fiuorobarbituric acid was recovered. The solid was foundsoluble in 10% sodium carbonate solution, hot water, and hotisopropanol, and insoluble in 3 N HCl, benzene, cold water, and coldisopropanol. The 5-ethyl-5-fluorobarbitaric acid product was purified bydissolving it in sodium carbonate solution and reprecipitating it withconcentrated hydrochloric acid. The product melted at 204-205.5 C.Analysis.Calculated for C6H7O3N2FZ N, 16.1; F, 10.9. Found: N, 16.25; F,10.75. The product is useful like barbituric acid derivatives and as anintermediate for organic synthesis.

Example 7 6.6 g. of CH (CN) malononitrile and 5 g. of sodium metal weredissolved in 100 ml. of absolute ethanol. ClO F gas was bubbled into thesolution with stirring at a temperature of about 35 C. until thereaction mass became substantially neutral. The solvent was distilledoff and the product was extracted with ether. The extract was dried overMgSO filtered and concentrated under vacuum. The final product wasidentified as the fluorine derivative of the starting malononitrile byfusion with sodium metal followed by precipitation of the fluorine byC(NO3)3.

The process of our invention provides a means for substituting fluorineinto the active methyl, methylene and methinyl group of a wide varietyof compounds. The resulting products in many cases are compounds whichpreviously were unknown and unavailable, but which now are for the firsttime disclosed as a result of our invention. Our process is thusadvantageous for the preparation of known as well as novel compounds.

Following substantially the same procedure as described in Example 1,our method of fluorination using perchloryl fluoride as the fiuorinatingagent can be used advantageously for the fluorination of the activehydrogen compounds shown in the following examples.

In the examples, X, Y and Z, as previously described, representhydrogen, halogen, phenyl or aliphatic radical of not more than 3 carbonatoms, the carbon skeleton of which has attached to it radicals selectedfrom the group hydrogen and halogen.

Active Hydrogen Alkali Metal Perehloryl Example Number Compound Base,Moles Fluoride, Product Moles 8 C OX C 0 OX CH, 2Na0 0 11 2 CF; 30 CY 30O Y 9 COOCzHg COOCQIR Hz 2NaO C 11 2 (BF: COOCH; COOCHa 10 COCO-C 11COOCflL- CH 2K0 C 11 2 F2 COOCaH'l 3OOCaH1 11 CN CN II-I 2NaO CH3 2 (JIM30 0 X 30 OX 12 ON ON (3H 2NaOC H 2 CF; 30 OH 30 011 13 ON ON (3H 2K001H; 2 (31 2 COOCzHg COOC H 14 C 0 OX C 0 OX I CC H KOCH: 1 F( JC I-I CO OY C O 0 Y 15 000011101 COOCI-I Cl HC-CE3 NaO C311 1 FCCH;

OOCaH7 COOCaH1 16 C 0 OX C 0 OX CH ZKNH; 2 C F1 (31' CY t) t 17 COOCHaCOOCHa CH1 2Na0 C111 2 C F; C-CHz-CH3CHC13 ('J-CH -CH;CH C]: ll 1% 18000C311; COOCzH'I CH; 2Na0 01H; 2 CF; ]CHs l-011a ti 1% 19 ON ON JHQ2NaO C 11 2 JF 10 0 CH; C O 0 011a 20 CN CN (3H1 2Na0 CH3 2 F; 6N NActive Hydrogen Alkali Metal Perchloryl Example Number Compound Base,Moles Fluoride, Product Moles 21 C 0 OX 0 0 OX l X 1 X H-C-GY NBOCRHB 1B OG-J (L0 0 Y Z 30 O Y Z H-lQ-Cl N8OC2H5 1 F(LCl LOOCzH (Lo oa s 2300002115 COOC2H5 H-CCCH3 NaO C H 1 FC 1C-OHa ll ll 0000 11 COOCzH;

24 COOCzHa COOC2H5 HCCH;OH=CH NaOC H 1 FC ICHZCH=OH1 COOCzHa (1000 11 25N02 N0 JHz 2NaOC2H 2 3F, C 0 OX ('30 OX 26 NO: NO; 1H 2NaO C 11 2 3F: 30O CH; O0 0 CH:

27 N02 N0 (7H1 2K0 CaH7 2 Fg 6N JN 28 ON CN #11, 2NaOCzH 2 +F2 29 GN ON(:JH; 2N8NH1 2 (13F:

m 2Na0 C2115 2 W l'm, E1,

2Na0 C H 2 3H: I /F s2 n 2Na0 0 11 2 K W ("1H3 (15F:

33 CH3 CH (5:0 6:0 311: 2Na0 C2115 2 31 (1:0 =o 5H3 is Active HydrogenAlkali Metal Perchloryl Example Number Compound Base, Moles Fluoride,Product Moles 34 CH3 CH3 5:0 81:0 JH ZNaO CH1 2 C F i= i=0 $3137 (5311735 0 CH 0 CH3 6:8 (1:8 1H: 2NaOC H 2 )Fl C=S C=S CH )CHa Example 36 20The product was 88 g. of diethyl 2-fluoro-2-phenylmalo- To 89 g. (0.89mole) of 2,4-pentanedione in 500 ml. of absolute ethanol were addedportionwise 102 g. (1.9 moles) of sodium methylate while addingperchloryl fluoride at a reaction temperature of 10 C. to 0 C. Whensufiicient perchloryl fluoride had been passed into the mixture to reactwith all the base present, additional sodium methylate was added inprogressively smaller portions, bringing the reaction mixture to theneutral point with perchloryl fluoride before addition of eachsucceeding portion. The product was 94 g. of 3,3-difiuoro-2,4-pentanedione, a colorless liquid; B.P. 114 C. with slow decomposition;61 C./102 mm.; 11 1.3680.

Analysis.Calculated for C H F O C, 44.12; H, 4.45. Found: C, 44.33; H,4.93.

The infrared spectrum showed absorption at 5.71 A strong band at 8.93was found and is associated with carbonfluorine stretching frequency.

Example 37 The 2,4-dinitrophenylhydrazone derivative of3,3-difluoro-2,4-pentanedione.

was prepared by reacting 3,3-difiuoro-2,4-pentanedione and2,4-dinitrophenylhydrazine in aqueous alcohol and dilute sulfuric acidat about C.-40 C. Yellow plates of the above product were recovered,M.P. 124125 C. Analysis.Calculated for C H F N O N, 17.72. Found: N,17.92.

Example 38 Using the procedure of Example 36, diethyl Z-phenylmalonate,87 g. (0.37 mole), in 300 ml. of absolute ethanol, was reacted withperchloryl fluoride While add ing 24 g. (0.44 mole) of sodium methylateportionwise.

nate, a colorless oil; B.P. 124/0.3 mm.; n 1.4792.

Analysis.Calculated for C H FO C, 61.41; H, 5.95. Found: C, 61.59; H,5.88.

Absorption in the infrared spectrum characteristic of the carbonyllinkage appears at 5.69,u.. This compares with absorption at 5.76 in thestarting material, diethyl phenylmalonate.

Example 39 Z-fluoro-2-phenylmalonamide was prepared by reaction ofdiethyl 2-fluoro-2-phenylmalonate with liquid ammonia containing sodium.White needle crystals, M.P. 204- 205 C.

Analysis.Calculated for C H FN O C, 55.10; H, 4.62; N, 14.29. Found: C,55.42; H, 5.19; N, 14.45.

Diethyl Z-fiuoro-2-phenylrnalonate, 2-fluoro-2-phenylmalonamide,3,3-difiuoro-2,4-pentanedione and the 2,4- dinitrophenylhydrazonederivative of 3,3-difluoro-2,4-pentanedione are useful intermediates inthe preparation of barbiturate type pharmaceutical compounds.

This application is a continuation-in-part of Serial No. 685,807, filedSeptember 24, 1957, abandoned. It is also a divisional application ofSerial No. 762,248, filed September 22, 1958, now U.S. Patent No.3,030,408.

Many diiferent embodiments of this invention may be made withoutdeparting from the spirit and scope of it, and it is to be understoodthat our invention includes also such embodiments and is not limited bythe above description.

We claim:

2-fluoro-2-phenylmalonamide.

References Cited in the file of this patent OTHER REFERENCES Henne etal.: Jour. Am. Chem. Soc., 1548-1550 (1948).

vol 70, pages UNITED srlTEs PATENT OFFICE CERTIFICATE OF CORRECTIONPatent N00 3,,l41 O4O July 14 1964 Charles E, Inman et ale It is herebycertified that error appears in the above numbered patant requiringcorrection and that the said Letters Patent should read as correctedbelow Column 2 lines 49 to 52,, the figure should appear as shown belowinstead of as in the patent:

same column 2 lines 55 to 61 the figures should appear as shown belowinstead of as in the patent:

X X l!/ CN; C= O; C=C\ Z LIZ X Y 2* r1 C=O; CZ:S; C S; and -NO column 3line 10 for "are" read is column 6 line 64 for fluorobarbitaric read--fluorobarbituric columns 7 and 8 in the table under the heading"Active Hydrogen Compound" and opposite Example Number 10-" the figureshould a appear as shown below instead of as in the patent:

( I'OOC H CH2 COOC3H7 same table under the heading "Active HydrogenCompound and opposite "Example Number 14" the figure should appear asshould appear as shown below ins shown below instead of as in thepatent:

columns 9 and 10 in the table under the heading "Active HydrogenCompound" and opposite "Example Number 28" the figure tead of as in thepatent:

Signed and sealed this 24th day of November 1964(,

(SEAL) Attest:

EDWARD Jo BRENNER ERNEST W, SWIDER Attesting Officer Commissioner ofPatents

